Aminoketoalcohol and process for the manufacture of same



Patented May 30, 1933 UNITED STATES PATENT OFFIC KURT WARNA'I', OF BASEL, SWITZERLAND,

OF NUTLEY, NEW JERSEY, A CORPORATION OF NEW AssIeNon 'ro nomANN-m some 1110.,

ERSEY mmoxnironnconon Ann rnoonss FOR THE mmurAc'runn or SAME e Io Drawing. Application filed December 370, 1930, Serial No. 505,671, and in Germany January 18,

It has been found, that aminoalcohols readily react with a-halog'enketones forming aminoketoalcohols. By aminoketoalcohols are understood compounds in which the n1- ''8 trogen atom,,which is not connected to a benzene ring, carries an alkyl radical and two aralkyl radicals, of which latter one contains an aliphaticketo group'and'the other an ali- V phatic hydroxyl group. The following equation illustrates the reaction between ephedrine, and l-phenyl-l-oXo-2-brompropane abrompropiophenone) according to Example 1: r

omEonononwmy-i +BrOH(OH;)COG|H l-ephedrine (l-phenylpropanolmethylamlne) C 11 =-CHOH.CH CH -N (CH CH CH5) CO C 11 HBr' phenylpropanolphenylpropanonmethylamine u-brompropiophenone The transformation" is carried out by using an excess of the aminoalcohol. Instead of using an excess of the aminoalcohol, the condensationmay be carried'out with the aid of alkali. e

The new compounds are easily soluble in the usual organic solvents, for instance alcohol, ether, benzene, chloroform; in water they are insoluble. With acids they mostly form well crystallized salts which are soluble in water. Most of the new compounds have a decided action on the respiratory centre.

The new compounds are to be used as such for therapeutic purposes or as intermediates for the manufacture of pharmaceutical preparations. i

E wample *1 16 parts of l-phedrine are boiled in 80 parts 40 of benzene with 12 parts of '1-phenyl-l-oxo-2- brompropane (a-bIOIIlPI'OPlOPllBHOIlG) for 5 .hours; Without removing the precipitated ephedrine salt the reaction-mixture is then treated with an acid, made alkaline and exhaustively extracted with ether. The unchanged ephedrine is removed by vacuum distillation and the residue recrystallized from 'methyl alcohol. The condensationproduct thusobtained is soluble in ether, benzene, alcohol and chloroform; it is insoluble in water and melts at 9293 C; It is op tically inactive.

The hydrochloride is exceedingly soluble in water, very easily soluble in alcohol, and melts at 194 C. 1

Example 2 36 parts of d-pseudo-ephedrine are boiled in 150 parts of benzenewith 23, parts ofabrompro'piophenone for 5 hours and the precipitated pseudo-ephedrine is removed. Y The reaction-product is then acidified witha lit-v tle hydrochloric acid, whereby the hydrochloride of the condesation-product is precipitated as crystals. These are removed and recrystallized from water,"in which *they are rather ditficultly soluble. Meltingpoint'206 C. [411 12.6. Y Y

The base is easily soluble in benzene, alcohol and chloroform, insoluble in Water and melts at 156 Example I e 33 parts of l-ephedrine base are boiled in 100 parts of benzene and 100 parts of water with 43 parts of a-brompropiophenone and a concentrated aqueous solution of 12 parts of potassium hydroxide is added. The boiling -is continued for 3 to 4 hours, the bases are taken up in acid and, while cooling, made alkaline with a solution of sodium hydroxide. An oil is separated from the reactionproduct. It is dissolved in hot methyl alcohol; on cooling, the crystalline condensation-product is precipitated in good yield. The compound meltsat 126 C.; it is easily soluble in chloroform and ether, insoluble in Water! The hydrochloride is very easily soluble in water and melts at 192193 C. The specific rotation of its aqueous solution is [a] +93. Inthe mother liquors a little of the racemic compound of meltin point 9293 C. and some unchanged ep edrine are found, the latter is'recovered by vacuum distillation. 28 parts of the optically active condensation-product and 3 parts of the racemic compound were obtained, while 7 palgs of unchanged l-ephedrine were recovere I Ewample 4 33 parts of d-pseudo-ephedrine base are heated in 100 parts of benzene and 100 parts of'water with 43 parts of oc-bIOHlPIOPlO- phenone and a concentrated aqueous solution of 8 parts of sodium hydroxide is added. The'boiling is continued for 3 hours.

On acidifying with hydrochloric acid, con-- parts of l-ephedrine base with the addition of 6 parts of sodium carbonate are boiled with 22 parts of a-brompropiophenone in 300 parts of benzene for 4 hours. The bases are then taken up with acid, made alkaline with a solution ofsodium hydroxide and the precipitated oil is crystallized from methyl alcohol. The optically active compound melting at 126 0., which is described in Example 3, is obtained; the yield is 10' parts. I

Example 6 5 parts ofd,l-ephedrine hydrochloride, 5 partsof a-bromacetophenone, 2.8 parts of potassium hydroxide are shaken in parts of, water and .20 parts of benzene, whereupon reaction sets in with evolution of heat. The boiling is continued foran hour, the product shaken with ether and hydrochloric acid and the base precipitated by a solution of sodium hydroxide from thehydrochloric acid solution. The base is recrystallized from methyl alcohol and melts at 76 C. It is'easily soluble in ether and benzene.

Thelhydrochloridemelts at 146 C. and is easily soluble in water. I

Emample 7 Example 8 3 parts of B-phenylethanolmethylamine, 1.2 parts of potassium hydroxide and 4 parts 6., which is described in Example 2, are precipitated for purifica-.

The

with water and dissolved in warm dilute hy drochloric acid. 011 cooling the hydrochloride of'the new compound crystallizes from the solution. It melts at l67168 0., after sintering atlOQ C. Thebase is easilysolu: ble in alcohol, ether, benzene and chloroform; it is insoluble in Water and melts at 80 C.

Example .9

,8-ph'enylethanolmethylamine hydrochloride are 'boiled'with 2. .tpartsof potassium hydroxide and 4.5 parts of ibrompropiophenone in 10 parts of water and 10 parts of benzene for 4 hours. It is worked up in the same manner as in Example 8. The hydrochloride of the new compound is re-. crystallized from water. It melts at 177", C. The base is easily soluble in alcohol, ether, chloroform and benzene, insoluble in water, and melts at 110 C.

claim: I 1. As new products the aminol retoalcohol's of the formula CGH5CHOH-CH (R N on cn (R B being hydrogen or alkyl; the new products being readily soluble in alcohol, ether, benzene, and chloroform, but insolublein water; the compounds forming with acids well crystallized water soluble salts, having in general a decided action on. the respiratory center.

2. As new products the ephedrine derivatives of the formula CGH5-CHOHCH(CH3)N(CH3)CH(R)-CO-C6H5, B being hydrogen or alkyl, the new products being easily soluble in alcohol, ether, benzene, and chloroform. but insoluble in water; the compounds forming with acids well crystallized water soluble salts, having in general decided action on the respiratory center.

3. As new products the ephedrine derivatives of the formula C H CHOHCH(CEI )-N(CH )CH(CH )COC H;, the new products being easily soluble in alco hol, ethenbenzene and chloroform, but insoluble in water; the compounds forming with acids well crystallized water soluble salts, having in general a decided'action on the respiratory center.

4. N 0c benzoylethyl l ephedrine having the formula v 5. A process for the manufacture of N- aryl-alkylol-N-arylalkylone amines which 4 parts of half an hour and the bases are 7 consists in condensing a substance selected from the group consisting of oz phenyl ethanol methyl amine and B phenylethanol methyl amine with a compound of the following general type where R represents hydrogen or a hydrocarbon radical of the lower aliphatic series.

6. A process for the manufacture of N aryl-alkylol-N-aryalkylone amines which consists in condensing a substance selected from the group consisting of a phenyl ethanol methyl amine and B phenyl ethanol methyl 5 amine with a compound of the following general type where R represents hydrogen or a hydrocarbon radical of the lower aliphatic series, in the presence of alkali.

7 A process for the manufacture of ephedrine N-acyl phenones, which consists in condensing ephedrine with a compound of the following general type where R represents hydrogen or a hydrocarbon radical of the lower aliphatic series.

8. A process for the manufacture of ephedrine N-acyl phenones, which consists in condensing ephedrine with a compound of the following general type where R represents hydrogen or a hydrocarbon radical of the lower aliphatic series, in the presence of alkali.

9. A process for the manufacture of ephedrine N-propiophenone which consists in con- 40 densing ephedrine with a brompropiophenone.

10. A process for the manufacture of ephedrine N-propiophenone which consists in condensing ephedrine with a brompropiophenone in the presence of alkali.

11. Process for the manufacture of phenylpropanolphenylpropanonmethylamlne, which consists in condensing l-ephedrine with oz-bI'OIIlPI'OPlOPhBIlOIlG.

12. Process for the manufacture of l-phenylpropanolphenylpropanonmethylamine, which consists in condensing l-ephedrine with a-bIOIIlPIOPiOPllBHOIlG in the presence of alkali.

5 In witness whereof I have hereunto set my hand.

KURT WARNAT. 

